We request funds to purchase a state-of-the-art commercial confocal macroscope configured to support a diverse portfolio of basic and translational approaches that require imaging of biological and disease processes at the cellular, tissue, organ, and whole animal levels. The instrument, a Nikon AZ100-C2Si Macro Confocal Microscope System, is one-of-a-kind in being specially designed for high-resolution fluorescent imaging at a macroscopic scale in three dimensions through real time. The Nikon AZ-C2Si will meet the needs of its Users in several fundamental ways. Unlike standard confocals, this instrument has a large field of view (up to 60 mm diagonal) and large working distances (up to 54 mm). These are orders of magnitude beyond other confocals and will enable Users to image a wide range of samples that are wet or dry, cleared or native, very thick, and mounted or incubating in any format (e.g., dish, plate, and microfluidic environment) without interfering with the optics. An automated smooth zooming optical system (8:1 range) will allow for time-lapse experiments using multiple magnifications in the same sample without objectives rotating in and out of the light path. We include a motorized stage, a climate chamber for culture experiments, and a four-laser configuration for detecting all commonly used dye combinations and/or fluorescent protein variants with maximum resolution and imaging sensitivity. A true spectral system removes auto-fluorescence and cross talk between fluorophores, permits 3D optical sectioning, and eliminates out of focus light. No other instrument at UCSF or on the market has all the same capabilities and flexibility. As detailed in the proposal, Users need these unique features to accelerate discoveries on projects that involve large populations of live and fixed cells, tissues, organs, and whole animals. This proposal is a collaboration of basic, translational, and clinical scientists who use a variety of model systems in birds and mammals. The Nikon AZ-C2Si will reside in a recently remodeled laboratory on the Parnassus Heights Campus adjacent to, and operating as part of, the Biological Imaging Development Center (BIDC), which is a highly successful core facility that functions with strong institutional support and administrative oversight at UCSF. The Nikon AZ-C2Si will provide for the first time at UCSF a much-needed suite of features and functions that will lead to novel discoveries and dramatic research advances in areas such as tissue engineering and regeneration, stem cell differentiation, embryonic patterning and birth defects, tumor progression and metastasis, and organ development and repair. Access, training, and recharge will be managed by the BIDC, which has a proven track record of moving innovative technology into areas currently constrained by technical limitations of existing instruments. This application and instrument will support 11 NIH- funded investigators and their laboratories, and facilitate advances on at least 23 NIH-funded R- and U-coded projects. The Nikon AZ-C2Si will also be available to others within the UCSF community. Thus, this shared instrument will address unmet needs of its Users and accelerate the pace of biomedical research at UCSF.